EP2956135B1 - Heterocyclic amide derivatives as p2x7 receptor antagonists - Google Patents

Heterocyclic amide derivatives as p2x7 receptor antagonists Download PDF

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Publication number
EP2956135B1
EP2956135B1 EP14706331.7A EP14706331A EP2956135B1 EP 2956135 B1 EP2956135 B1 EP 2956135B1 EP 14706331 A EP14706331 A EP 14706331A EP 2956135 B1 EP2956135 B1 EP 2956135B1
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Prior art keywords
thiazole
carboxamide
dihydro
tetrahydrobenzo
dichloro
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German (de)
English (en)
French (fr)
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EP2956135A1 (en
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Kurt Hilpert
Francis Hubler
Dorte Renneberg
Simon STAMM
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Idorsia Pharmaceuticals Ltd
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Actelion Pharmaceuticals Ltd
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    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
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    • C07D277/62—Benzothiazoles
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    • C07D277/62—Benzothiazoles
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    • C07D277/82—Nitrogen atoms

Definitions

  • the present invention relates to heterocyclic amide derivatives of formula (I) and their use as pharmaceuticals.
  • the invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of formula (I), and especially their use as P2X 7 receptor antagonists.
  • P2X 7 receptors belong to the family of P2X ionotropic receptors that are activated by extracellular nucleotides, in particular adenosine triphosphate (ATP).
  • P2RX7 is distinguished from other P2X family members by the high concentrations (mM range) of ATP required to activate it and its ability to form a large pore upon prolonged or repeated stimulation ( North, R. A., Physiol. Rev. 2002, 82(4), 1013-67 ; Surprenant, A., Rassendren, F. et al., Science 1996, 272(5262), 735-8 ; Virginio, C., MacKenzie, A. et al., J.
  • P2RX7 is present on many cell types, especially ones known to be involved in inflammatory and immune processes. This is reflected within both the periphery and the CNS as Lipopolysaccharide S (LPS) priming of monocytes and microglia followed by ATP stimulation has been shown to lead to the local release and processing of IL1 ⁇ and other family members including IL18 through a P2RX7 mediated mechanism. Indeed mice lacking the P2X7 receptor are unable to release IL1 ⁇ following LPS priming and ATP stimulation providing further evidence of its role in this pathway ( Solle, M., Labasi, J. et al., J. Biol.
  • LPS Lipopolysaccharide S
  • diseases associated with the central nervous system such as stroke or injury and diseases associated with neuro-degeneration and neuroinflammation such as Alzheimer's disease, Huntington's disease, epilepsy, Amyotrophic lateral sclerosis, acute spinal cord injury additionally to meningitis, sleep disorders, mood and anxiety disorders as well as chronic and neuropathic and inflammatory pain.
  • peripheral inflammatory disorders and autoimmune diseases including but not limited to rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, chronic obstructive pulmonary disease, airways hyper-responsiveness, septic shock, bronchitis, glomerulonephritis, irritable bowel disease, skin injury, lung emphysema, Limb girdle dystrophy type 2B, fibrosis, Syndrome of synovitis Acne Pustulosis, atherosclerosis, burn injury, spinal cord injury, Hyperostosis Osteitis, Crohn's disease, ulcerative colitis, growth and metastases of malignant cells, myoblastic leukaemia, diabetes, trauma, meningitis, osteoporosis, burn injury, ischemic heart disease, and varicose veins and trauma, are all examples where the involvement of P2X7 channels has been implicated.
  • P2X7 antagonists that can be efficiently used in treating neuropathic pain, chronic inflammatory pain, inflammation, and neurodegenerative conditions.
  • Indole carboxamide derivatives which are also P2X 7 receptor antagonists, have been for instance disclosed in WO 2009/108551 .
  • Pyrazolyl-acetamide derivatives as P2X 7 receptor antagonists are described in WO 2008/138876 and in L.J. Chambers et al., Bioorg. Med. Chem. Lett., 2010, 20, 3161-3164 ; the article additionally discloses thiazolyl-acetamide derivatives.
  • Other P2X 7 receptor antagonists with a heterocyclic amide structure have been disclosed in WO 2013/014587 and in WO 2013/108227 .
  • the compounds of formula (I) according to embodiment 1) may contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms. Substituents at a double bond may be present in the (Z)- or ( E )-configuration unless indicated otherwise.
  • the compounds of formula (I) may thus be present as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art.
  • variable attached bonds may be used for substituents or groups.
  • the substituent or group is attached to any carbon atom of the ring system to which the variable attached bond is drawn into, provided that said carbon atom is not already specifically substituted.
  • any group R 3 may be attached to any carbon atom of the phenyl ring of formula (I) which is not already substituted.
  • formula (I) therefore encompasses the following four formulas:
  • the second R 3 group may be attached to any carbon atom of the phenyl ring of any one of formulas (I-1), (I-2), (I-3) or (I-4), which carbon atom is not already substituted, wherein the two R 3 groups may be the same or different.
  • the R 3 group is absent.
  • Definitions provided herein are intended to apply uniformly to the compounds of formulae (I), (I-1), I-2), (I-3), (I-4), (I Bn ), (I XO ) and (I xc ), as defined in any one of embodiments 1) to 26), and, mutatis mutandis, throughout the description and the claims unless an otherwise expressly set out definition provides a broader or narrower definition. It is well understood that a definition or preferred definition of a term defines and may replace the respective term independently of (and in combination with) any definition or preferred definition of any or all other terms as defined herein.
  • alkyl refers to a straight or branched chain alkyl group containing one to four carbon atoms.
  • (C x -C y )alkyl refers to an alkyl group as defined before containing x to y carbon atoms.
  • a (C 1 -C 4 )alkyl group contains from one to four carbon atoms.
  • Representative examples of alkyl groups include methyl, ethyl, n -propyl, iso -propyl, n -butyl, iso -butyl, sec .-butyl and tert .-butyl.
  • R 1 represents "(C 1 -C 2 )alkyl” the term means (C 1 -C 2 )alkyl groups as defined above. Examples of said groups are methyl and ethyl. Preferred is methyl.
  • R 3 represents "(C 1 -C 4 )alkyl”
  • the term means (C 1 -C 4 )alkyl groups as defined above. Examples of said groups are methyl, ethyl, n -propyl, iso -propyl, n -butyl, iso -butyl, sec .-butyl and tert .-butyl. Preferred is methyl.
  • R 4 represents "(C 1 -C 4 )alkyl” the term means (C 1 -C 4 )alkyl groups as defined above.
  • Examples of said groups are methyl, ethyl, n -propyl, iso -propyl, n -butyl, iso -butyl, sec .-butyl and tert .-butyl. Preferred is methyl.
  • alkoxy refers to an alkyl-O- group wherein the alkyl group is as defined above.
  • (C x -C y )alkoxy refers to an alkoxy group as defined before containing x to y carbon atoms.
  • a (C 1 -C 4 )alkoxy group contains from one to four carbon atoms.
  • Representative examples of alkoxy groups include methoxy, ethoxy, n -propoxy, iso -propoxy, n -butoxy, iso -butoxy, sec .-butoxy and tert .-butoxy.
  • R 3 represents "(C 1 -C 4 )alkoxy"
  • the term means (C 1 -C 4 )alkoxy groups as defined above. Examples of said groups are methoxy, ethoxy, n -propoxy, iso -propoxy, n -butoxy, iso -butoxy, sec .-butoxy and tert .-butoxy. Preferred is methoxy.
  • hydroxy-(C x -C y )alkyl refers to an alkyl group as defined before containing x to y carbon atoms in which one hydrogen atom has been replaced with hydroxy.
  • a hydroxy-(C 1 -C 3 )alkyl group contains from one to three carbon atoms in which one hydrogen atom has been replaced with hydroxy. Examples of said groups are hydroxy-methyl, hydroxy-ethyl and hydroxy-propyl.
  • R 1 represents "hydroxy-(C 1 -C 2 )alkyl” the term means hydroxy-(C 1 -C 2 )alkyl groups as defined above.
  • Representative examples of said groups are hydroxy-methyl, 1-hydroxy-ethyl and 2-hydroxy-ethyl. Preferred is hydroxy-methyl.
  • R 3 represents "hydroxy-(C 1 -C 3 )alkyl" the term means hydroxy-(C 1 -C 3 )alkyl groups as defined above.
  • Representative examples of said groups are hydroxy-methyl, 1-hydroxy-ethyl, 2-hydroxy-ethyl, 1-hydroxy-prop-1-yl, 2-hydroxy-prop-1-yl, 3-hydroxy-prop-1-yl, 1-hydroxy-prop-2-yl and 2-hydroxy-prop-2-yl. Preferred is hydroxy-methyl.
  • (C 1 -C 2 )alkoxy-(C 1 -C 2 )alkyl refers to an alkyl group as defined before containing one or two carbon atoms in which one hydrogen atom has been replaced with (C 1 -C 2 )alkoxy as defined before. Examples of said groups are methoxy-methyl, methoxy-ethyl, ethoxy-methyl and ethoxy-ethyl.
  • R 3 represents "(C 1 -C 2 )alkoxy-(C 1 -C 2 )alkyl” the term means "(C 1 -C 2 )alkoxy-(C 1 -C 2 )alkyl groups as defined above.
  • Representative examples of said groups are methoxy-methyl, 1-methoxy-ethyl, 2-methoxy-ethyl, ethoxy-methyl, 1-ethoxy-ethyl and 2-ethoxy-ethyl. Preferred is methoxy-methyl.
  • hydroxy-(C x -C y )alkoxy refers to an alkoxy group as defined before containing x to y carbon atoms in which one hydrogen atom has been replaced with hydroxy.
  • a hydroxy-(C 2 -C 3 )alkoxy group contains from two to three carbon atoms in which one hydrogen atom has been replaced with hydroxy. Examples of said groups are 2-hydroxy-ethoxy, 2-hydroxy-prop-1-oxy, 3-hydroxy-prop-1-oxy and 1-hydroxy-prop-2-oxy.
  • R 3 represents "hydroxy-(C 2 -C 3 )alkoxy"
  • the term means hydroxy-(C 2 -C 3 )alkoxy groups as defined above. Representative examples of said groups are 2-hydroxy-ethoxy, 2-hydroxy-prop-1-oxy, 3-hydroxy-prop-1-oxy and 1-hydroxy-prop-2-oxy. Preferred is 2-hydroxy-ethoxy.
  • hydroxy-(C 2 -C 3 )alkoxy-(C 1 -C 2 )alkyl refers to an alkyl group as defined before containing one or two carbon atoms in which one hydrogen atom has been replaced with hydroxy-(C 2 -C 3 )alkoxy as defined before.
  • Examples of said groups are (2-hydroxy-ethoxy)-methyl, 1-(2-hydroxy-ethoxy)-ethyl, 2-(2-hydroxy-ethoxy)-ethyl, (2-hydroxy-prop-1-oxy)-methyl, (3-hydroxy-prop-1-oxy)-methyl, (1-hydroxy-prop-2-oxy)-methyl, 1-(2-hydroxy-prop-1-oxy)-ethyl, 1-(3-hydroxy-prop-1-oxy)-ethyl, 1-(1-hydroxy-prop-2-oxy)-ethyl, 2-(2-hydroxy-prop-1-oxy)-ethyl, 2-(3-hydroxy-prop-1-oxy)-ethyl, and 2-(1-hydroxy-prop-2-oxy)-ethyl.
  • R 3 represents "hydroxy-(C 2 -C 3 )alkoxy-(C 1 -C 2 )alkyl
  • the term means hydroxy-(C 2 -C 3 )alkoxy-(C 1 -C 2 )alkyl groups as defined above.
  • Representative examples of said groups are (2-hydroxy-ethoxy)-methyl, 1-(2-hydroxy-ethoxy)-ethyl, 2-(2-hydroxy-ethoxy)-ethyl, (2-hydroxy-prop-1-oxy)-methyl, (3-hydroxy-prop-1-oxy)-methyl, (1-hydroxy-prop-2-oxy)-methyl, 1-(2-hydroxy-prop-1-oxy)-ethyl, 1-(3-hydroxy-prop-1-oxy)-ethyl, 1-(1-hydroxy-prop-2-oxy)-ethyl, 2-(2-hydroxy-prop-1-oxy)-ethyl, 2-(3-hydroxy-prop-1-oxy)-ethyl, and 2-(1-hydroxy-prop-2-oxy)-ethyl.
  • Preferred is (2-hydroxy-ethoxy)-methyl.
  • (C 3 -C 6 )cycloalkyl refers to a cycloalkyl group with 3 to 6 carbon atoms.
  • Examples of (C 3 -C 6 )cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 3 represents "(C 3 -C 6 )cycloalkyl” the term means (C 3 -C 6 )cycloalkyl groups as defined above. Representative examples of said groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Preferred is cyclopropyl.
  • (C x -C y )fluoroalkyl refers to an alkyl group as defined before containing x to y carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluoro.
  • a (C 1 -C 3 )fluoroalkyl group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluoro.
  • R 3 represents "(C 1 -C 3 )fluoroalkyl” the term means (C 1 -C 3 )fluoroalkyl groups as defined above.
  • Representative examples of said groups are difluoromethyl, trifluoromethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl. Preferred is trifluoromethyl.
  • R 4 represents "(C 1 -C 3 )fluoroalkyl" the term means (C 1 -C 3 )fluoroalkyl groups as defined above.
  • Representative examples of said groups are difluoromethyl, trifluoromethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl. Preferred is trifluoromethyl.
  • (C x -C y )fluoroalkoxy refers to an alkoxy group as defined before containing x to y carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluoro.
  • a (C 1 -C 3 )fluoroalkoxy group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluoro.
  • R 3 represents "(C 1 -C 3 )fluoroalkoxy” the term means (C 1 -C 3 )fluoroalkoxy groups as defined above. Representative examples of said groups are difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy and 2,2,2-trifluoroethoxy. Preferred is trifluoromethoxy.
  • halogen means fluoro, chloro or bromo.
  • R 2 represents “halogen” the term means fluoro, chloro or bromo. Preferred is chloro.
  • R 3 represents “halogen” the term means fluoro, chloro or bromo. Preferred are chloro and bromo.
  • R 4 represents “halogen” the term means fluoro, chloro or bromo. Preferred is bromo.
  • the present invention also includes isotopically labelled, especially 2 H (deuterium) labelled compounds of formula (I), which compounds are identical to the compounds of formula (I) except that one or more atoms have each been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • Isotopically labelled, especially 2 H (deuterium) labelled compounds of formula (I) and salts thereof are within the scope of the present invention. Substitution of hydrogen with the heavier isotope 2 H (deuterium) may lead to greater metabolic stability, resulting e.g. in increased in-vivo half-life or reduced dosage requirements, or may lead to reduced inhibition of cytochrome P450 enzymes, resulting e.g. in an improved safety profile.
  • the compounds of formula (I) are not isotopically labelled, or they are labelled only with one or more deuterium atoms. In a sub-embodiment, the compounds of formula (I) are not isotopically labelled at all. Isotopically labelled compounds of formula (I) may be prepared in analogy to the methods described hereinafter, but using the appropriate isotopic variation of suitable reagents or starting materials.
  • salts refers to non-toxic, inorganic or organic acid and/or base addition salts, Lit. e.g. " Salt selection for basic drugs", Int. J. Pharm. (1986), 33, 201-217 .
  • compounds of formula (I) are suitable for use as medicaments.
  • compounds of formula (I) modulate the P2X 7 receptor, i.e. they act as P2X 7 receptor antagonists, and are useful for the prevention or treatment of diseases which are associated with the activation of the P2X 7 receptor such as pain; neurodegenerative and neuroinflammatory diseases; bone and joint diseases; obstructive diseases of the airways; cardiovascular diseases; eye diseases; skin diseases; abdominal and gastrointestinal tract diseases; genitourinary diseases; cancer; other auto-immune and allergic disorders; and other disorders with an inflammatory or immunological component.
  • the compounds of formula (I) according to any one of embodiments 1) to 26), or pharmaceutically acceptable salts thereof are suitable for the prevention or treatment of pain.
  • Pain refers to acute pain; chronic pain; pain associated with sprains and strains; chronic articular pain; pain associated with rheumatic fever; musculoskeletal pain; lower back and neck pain; inflammatory pain; neuropathic pain; visceral pain; pain associated with influenza or other viral infections; pain associated with cancer and tumor invasion; joint and bone pain; atypical facial pain; pain associated with migraine, toothache and dysmenorrhea; headache including tension headache and cluster headaches; pain associated with myocardial ischemia; pain associated with functional bowel disorders; sympathetically maintained pain; myositis; pain associated with cancer chemotherapy; and post operative pain.
  • Neuropathic pain includes especially diabetic neuropathy, sciatica, non-specific lower back pain, trigeminal neuralgia, multiple sclerosis pain, fibromyalgia, HIV-related neuropathy, post-herpetic neuralgia, and pain resulting from physical trauma, amputation, phantom limb syndrome, spinal surgery, cancer, toxins or chronic inflammatory conditions.
  • neuropathic pain conditions include pain associated with normally non-painful sensations such as "pins and needles" (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static, thermal or cold allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia).
  • Chronic articular pain conditions include especially rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis. Pain associated with functional bowel disorders includes especially non-ulcer dyspepsia, non-cardiac chest pain and irritable bowel syndrome.
  • Neurodegenerative and neuro-inflammatory diseases include Alzheimer's disease and other dementing disorders including, but not limited to, Creutzfeldt-Jakob disease (CJD) and new variant Creutzfeldt-Jakob disease (nvCJD); Amyotrophic lateral sclerosis, amyloidosis; multiple sclerosis and other demyelinating syndromes; cerebral atherosclerosis and vasculitis; temporal arteritis; myasthenia gravis; Huntington's disease; Lewy Body dementia; and Parkinson's disease.
  • CJD Creutzfeldt-Jakob disease
  • nvCJD new variant Creutzfeldt-Jakob disease
  • Bone and joint diseases include arthritides such as rheumatoid arthritis, osteoarthritis, gout or crystal arthropathy; intervertebral disc degeneration; temporomandibular joint degeneration; bone remodelling disease such as osteoporosis, Paget's disease or osteonecrosis; polychondritis; scleroderma; mixed connective tissue disorder; spondyloarthropathies; periodontal disease such as periodontitis; arthritides associated with or including osteoarthritis/osteoarthrosis, both primary and secondary to, for example, congenital hip dysplasia; cervical and lumbar spondylitis; Still's disease; seronegative spondyloarthropathies including ankylosing spondylitis, psoriatic arthritis, reactive arthritis and undifferenti
  • the compounds of formula (I) according to any one of embodiments 1) to 26), or pharmaceutically acceptable salts thereof are suitable for the prevention or treatment of obstructive diseases of the airways.
  • Obstructive diseases of the airways include asthma, including bronchial, allergic, intrinsic, and extrinsic asthma, exercise-induced, drug-induced (including aspirin and NSAID-induced) and dust- induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tub
  • Cardiovascular diseases include atherosclerosis, affecting the coronary and peripheral circulation; pericarditis; myocarditis; inflammatory and auto-immune cardiomyopathies including myocardial sarcoid; ischaemic reperfusion injuries; endocarditis, valvulitis, and aortitis including infective (for example syphilitic); vasculitides; and disorders of the proximal and peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and complications of varicose veins.
  • Eye diseases include blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; ulceris; anterior and posterior uveitis; choroiditis; autoimmune, degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; and infections of the eyes including viral, fungal, and bacterial infections.
  • the compounds of formula (I) according to any one of embodiments 1) to 26), or pharmaceutically acceptable salts thereof are suitable for the prevention or treatment of skin diseases.
  • Skin diseases include psoriasis, skin burn, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber-Christian
  • the compounds of formula (I) according to any one of embodiments 1) to 26), or pharmaceutically acceptable salts thereof are suitable for the prevention or treatment of abdominal and gastrointestinal tract diseases.
  • Abdominal and gastrointestinal tract diseases include hepatitis, including autoimmune, alcoholic and viral hepatitis; fibrosis and cirrhosis of the liver; cholecystitis; pancreatitis, both acute and chronic; non-inflammatory diarrhea; glossitis, gingivitis, periodontitis; oesophagitis, including reflux; eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, colitis including ulcerative colitis, proctitis, pruritis ani; Coeliac disease, irritable bowel disease/syndrome, and food-related allergies which may have effects remote from the gut, for example migraine, rhinitis or eczema; allograft rejection including acute and chronic allograft rejection following, for example, transplantation of kidney, heart, liver
  • the compounds of formula (I) according to any one of embodiments 1) to 26), or pharmaceutically acceptable salts thereof are suitable for the prevention or treatment of genitourinary diseases.
  • Genitourinary diseases include nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer; acute and chronic urethritis, hemorrhagic cystitis, prostatitis, epididymitis, oophoritis and salpingitis; vulvovaginitis; Peyronie's disease; and erectile dysfunction, both male and female.
  • the compounds of formula (I) according to any one of embodiments 1) to 26), or pharmaceutically acceptable salts thereof are suitable for the prevention or treatment of cancer.
  • the treatment of cancer includes the treatment of brain tumors, prostate, lung, breast, ovarian, bowel and colon, stomach, pancreatic, skin and bone marrow (including leukaemias) and lymphoproliferative systems, such as non-Hodgkin's and Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumor recurrences, and paraneoplastic syndromes.
  • the compounds of formula (I) according to any one of embodiments 1) to 26), or pharmaceutically acceptable salts thereof are suitable for the prevention or treatment of other auto-immune and allergic disorders.
  • Other auto-immune and allergic disorders include Hashimoto's thyroiditis, Graves' disease, Addison's disease, diabetes mellitus, idiopathic thrombocytopaenic purpura, eosinophilic fasciitis, hyper-IgE syndrome, and antiphospholipid syndrome.
  • the compounds of formula (I) according to any one of embodiments 1) to 26), or pharmaceutically acceptable salts thereof are suitable for the prevention or treatment of other disorders with an inflammatory or immunological component.
  • Other disorders with an inflammatory or immunological component include acquired immune deficiency syndrome (AIDS), leprosy, Sezary syndrome, and paraneoplastic syndromes.
  • AIDS acquired immune deficiency syndrome
  • leprosy leprosy
  • Sezary syndrome Sezary syndrome
  • paraneoplastic syndromes paraneoplastic syndromes.
  • the compounds of formula (I) according to any one of embodiments 1) to 26), or pharmaceutically acceptable salts thereof are suitable for the prevention or treatment of mood, depression, sleep and anxiety disorders.
  • the compounds of formula (I) according to any one of embodiments 1) to 26), or pharmaceutically acceptable salts thereof are suitable for the prevention or treatment of injury induced trauma and spinal cord injury.
  • compounds of formula (I) according to any one of embodiments 1) to 26), or pharmaceutically acceptable salts thereof are suitable for the prevention or treatment of diseases selected from one, several or all of the following groups of diseases and disorders:
  • compounds of formula (I) according to any one of embodiments 1) to 26), or pharmaceutically acceptable salts thereof are suitable for the prevention or treatment of diseases selected from one, several or all of the following groups of diseases and disorders:
  • the invention also relates to the use of a compound of formula (I) according to any one of embodiments 1) to 26) for the preparation of pharmaceutical compositions for the treatment and/or prophylaxis of the above-mentioned diseases.
  • the present invention also relates to pharmaceutically acceptable salts and to pharmaceutical compositions and formulations of compounds of formula (I) according to any one of embodiments 1) to 26).
  • a pharmaceutical composition according to the present invention contains at least one compound of formula (I) according to any one of embodiments 1) to 26) (or a pharmaceutically acceptable salt thereof) as the active agent and optionally carriers and/or diluents and/or adjuvants.
  • the compounds of formula (I) according to any one of embodiments 1) to 26) and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral (such as especially oral) or parenteral administration (including topical application or inhalation).
  • compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, "Pharmaceutical Manufacturing” [published by Lippincott Williams & Wilkins ]) by bringing the described compounds of formula (I) or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
  • the term “about” (or alternatively “around”) placed before a numerical value "X” refers in the current application to an interval extending from X minus 10% of X to X plus 10% of X, and preferably to an interval extending from X minus 5% of X to X plus 5% of X.
  • the term “about” (or alternatively “around”) placed before a temperature “Y” refers in the current application to an interval extending from the temperature Y minus 10 °C to Y plus 10 °C, and preferably to an interval extending from Y minus 5 °C to Y plus 5 °C.
  • room temperature refers to a temperature of about 25°C.
  • RT room temperature
  • the word "between” is used to describe a numerical range, it is to be understood that the end points of the indicated range are explicitly included in the range. For example: if a temperature range is described to be between 40 °C and 80 °C, this means that the end points 40 °C and 80 °C are included in the range; or if a variable is defined as being an integer between 1 and 4, this means that the variable is the integer 1, 2, 3, or 4.
  • the compounds of Formula (I) can be manufactured by the methods given below, by the methods given in the Examples or by analogous methods. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by a person skilled in the art by routine optimisation procedures.
  • the generic groups R 1 , R 2 , R 3 , R 4 , R 5 , n , m, p and X might be incompatible with the assembly illustrated in the schemes below and will therefore require the use of protecting groups (PG).
  • protecting groups is well known in the art (see for example " Protective Groups in Organic Synthesis", T.W. Greene, P.G.M. Wuts, Wiley-Interscience, 1999 ). For the purposes of this discussion, it will be assumed that such protecting groups are as necessary in place.
  • Compounds of formula (I) can be prepared by reaction of a carboxylic acid (II) with an amine (III) using standard amide coupling reagents such as EDC.HCl/HOBt, SiliaBond ® carbodiimide/HOAt, HATU/HOAt or PyBOP and a base like DIPEA in a solvent like DCM, THF or DMF preferably at temperatures between RT and 45°C (scheme 1).
  • standard amide coupling reagents such as EDC.HCl/HOBt, SiliaBond ® carbodiimide/HOAt, HATU/HOAt or PyBOP and a base like DIPEA in a solvent like DCM, THF or DMF preferably at temperatures between RT and 45°C (scheme 1).
  • thioamides (VI) can be prepared from the corresponding amides with P 4 S 10 or Lawesson's reagent in a solvent such as dioxane or toluene at temperatures between 60°C and 110°C. Saponification of the methyl ester (VII) can be performed under standard conditions such as LiOH in a THF/MeOH/H 2 O mixture, preferably at temperatures between 0°C and 45°C to form compounds of formula (IIa).
  • Compounds of formula (II), wherein R 4 represents chloro or bromo, respectively, can be prepared via a Sandmeyer type reaction of compounds of formula (VII), wherein R 4 represents amino using Cu(II)Cl 2 or Cu(II)Br 2 , respectively, and tBu-nitrite in MeCN at temperatures between RT and 60°C, followed by saponification with a base, such as LiOH in a solvent mixture like THF/MeOH/H 2 O at temperatures around RT (scheme 2).
  • a base such as LiOH in a solvent mixture like THF/MeOH/H 2 O at temperatures around RT (scheme 2).
  • Compounds of formula (II), wherein R 4 represents fluoro can be prepared by treating compounds of formula (VII), wherein R 4 represents amino with HBF 4 and NOBF 4 in a solvent like Et 2 O at temperatures between -50°C and RT, followed by saponification with a base, such as LiOH in a solvent mixture like THF/MeOH/H 2 O at temperatures around RT (scheme 2).
  • compounds of formula (II), wherein X represents -CH 2 - and R 4 represents hydrogen or amino can be prepared from the corresponding cycloalk-2-enone (VIII) by (1) addition of TMS-CN, catalyzed by Ni(cod) 2 and Gd(OTf) 3 in the presence of norbornadiene in a solvent such as THF at temperatures around RT and (2) bromination of the resulting silylenolether using an electrophilic bromine source such as NBS in a THF/H 2 O mixture at temperatures around 0°C to form ⁇ -bromoketone (IX) (scheme 3).
  • aminothiazoles (X) are prepared by condensation of the corresponding ⁇ -bromoketone (IX) with thiourea in a solvent such as dioxane at temperatures between 60°C and 100°C. Hydrolysis using aq. conc. HCl at temperatures between 60°C and 100°C form carboxylic acids (IIb), wherein R 4 represents amino.
  • aminothiazoles of formula (X) can be diazotized utilizing tBu-nitrite in THF at temperatures between 60°C and 80°C to provide the corresponding thiazoles. Hydrolysis of the nitrile group using aq. conc. HCl at temperatures between 60°C and 100°C form carboxylic acids (IIb), wherein R 4 represents hydrogen.
  • Cyclization precursor (XIII) can be prepared by (1) dechlorination using an alkyllithium species such as nBuLi in a solvent like THF at temperatures between -100°C and -40°C and (2) treatment with a fluoride source such as TBAF in a solvent like THF at temperatures between 0°C and RT.
  • alkyllithium species such as nBuLi
  • fluoride source such as TBAF
  • Cyclization to compounds of formula (XIV) can be performed with a base such as NaH or KOtBu in a solvent like DMF or tBuOH, respectively, or through a palladium mediated procedure using Pd(OAc) 2 , rac-2-(di-tert-butylphosphino)-1,1'-binaphthyl and a base like Cs 2 CO 3 in a solvent such as toluene at temperatures between 80°C and 110°C.
  • a base such as NaH or KOtBu in a solvent like DMF or tBuOH, respectively
  • Compounds of formula (IIc) are obtained by (1) removal of the THP protecting group under acidic conditions using, for instance, catalytic amounts of PTSA in a solvent mixture like THF/H 2 O at temperatures around RT, (2) a Mitsunobu reaction, and (3) hydrolysis of the nitrile using aq. conc. HCl at temperatures between 60°C and 100°C.
  • the Mitsunobu reaction can be carried out with acetone cyanohydrin, (nBu) 3 P and 1,1'-(azodicarbonyl)dipiperidine in a solvent like THF at temperatures between 0°C and RT.
  • Compound of formula (II), wherein X represents -O-, n represents 1, and R 4 represents hydrogen, can be prepared by reaction of 4-bromothiazole (XV) with the sodium salt of DL-1,2-isoproylideneglycerol at temperatures between 120°C and 150°C and subsequent bromination with an electrophilic bromine source such as NBS in a solvent like MeCN at temperatures between 0°C and RT (scheme 5).
  • the resulting 5-bromothiazole (XVI) is sequentially treated with (1) catalytic amounts of an acid such as PPTS in a solvent like MeOH at temperatures around reflux, (2) trimethyl orthoformate in a solvent like DCM at temperatures around RT, (3) AcBr in a solvent like DCM at temperatures around RT, and (4) a carbonate base such as K 2 CO 3 in a solvent like MeOH at temperatures around RT to form oxirane (XVII).
  • an acid such as PPTS in a solvent like MeOH at temperatures around reflux
  • trimethyl orthoformate in a solvent like DCM at temperatures around RT
  • AcBr in a solvent like DCM at temperatures around RT
  • a carbonate base such as K 2 CO 3
  • oxirane (XVII) in an ether solvent like THF is consecutively treated with an alkyl lithium reagent like nBuLi, a trialkylsilyl chloride like TIPSCI, and again with an alkyl lithium reagent like nBuLi to form dihydrofurothiazole (XVIII).
  • a two-step oxidation procedure utilizing (1) Dess Martin's reagent in a solvent like DCM at temperatures between 0°C and RT and (2) sodium chlorite in a buffered aq. solution with tBuOH as co-solvent and 2-methyl-2-butene as scavenger at temperatures around 0°C provides carboxylic acid (XIX).
  • Removal of the silyl protecting group to form a compound of formula (IId) can be performed with a fluoride source such as TBAF in a solvent like THF at temperatures between 0°C and RT.
  • Compounds of formula (III), wherein R 5 represents hydrogen and m represents 1 or 2 can be prepared from halides (XX), wherein X is preferably bromide or iodide and R a represents substituted phenyl-(C 1 -C 2 )alkyl, via a cyanation with NaCN or KCN in a solvent like CH 3 CN, EtOH or DMF preferably at temperatures between RT and 65°C (scheme 6).
  • the formed nitriles (XXI) can be reduced by hydrogenation with Raney Nickel as catalyst in a solvent such as NH 3 in MeOH.
  • a reducing agent such as BH 3 in THF preferably at temperatures between 0°C and 65°C or such as LiAlH 4 in a solvent like THF or Et 2 O preferably at temperatures between 0°C and RT can be used to form amines (IIIa).
  • compounds of formula (III), wherein R 1 and R 5 represent hydrogen and m represents 0 can be prepared by reduction of nitriles (XXI) wherein R a represents substituted phenyl (and notably by reduction with BH 3 in THF).
  • nitriles of formula (XXI) can be synthesized starting from carboxylic acids of formula (XXII), wherein R a represents substituted phenyl-(C 1 -C 2 )alkyl or substituted phenyl, by preparing the corresponding carboxamides (XXIII) under standard amide formation conditions, such as EDC.HCl/HOBt in a solvent like DCM or DMF and ammonia (scheme 6).
  • the carboxamides (XXIII) can be dehydrated to nitriles (XXI) using TFAA as dehydrating agent in the presence of Et 3 N in a solvent such as DCM preferably at temperatures between 0°C and RT.
  • compounds of formula (III), wherein R 5 represents hydrogen and m represents 0, 1, or 2 can be prepared in two steps from aldehydes of formula (XXIV), wherein R a represents substituted phenyl-(C 1 -C 2 )alkyl or substituted phenyl, via formation of the correponding oximes (XXV) using hydroxylamine hydrochloride under standard conditions such as in a solvent like EtOH at temperatures between RT and 60°C followed by a reduction of the respective oximes using zinc dust in a solvent like acetic acid preferably at temperatures between 0°C and RT or by using BH 3 in a solvent like THF preferably at temperatures between RT and 60°C (scheme 6).
  • R b represents a precursor to the R 5 NH-(CH 2 ) m -CHR 1 -moiety of compounds of formula (III) such as cyano, cyano-(C 1 -C 2 )alkyl, formyl, or PGN-(C 1 -C 3 )alkyl wherein PG represents an amine protecting group.
  • compounds of formula (III) may be prepared from compounds of formula (XXVI) according to the procedure described for the transformation of compounds of formula (XXI) to compounds of formula (IIIa) (scheme 6).
  • compounds of formula (III) may be prepared from compounds of formula (XXVI) according to the procedure described for the transformation of compounds of formula (XXIV) to compounds of formula (IIIa) (scheme 6).
  • R b represents a PGN-(C 1 -C 3 )alkyl group wherein PG represents a phthalimide protecting group
  • compounds of formula (III) may be prepared from compounds of formula (XXVI) by removal of the phthalimide group with, for instance, hydrazine in a solvent like EtOH at temperatures around RT.
  • the Suzuki reaction can be carried out for instance with (C 1 -C 4 )alkylboronic acid derivatives or (C 3 -C 6 )cycloalkylboronic acid derivatives (e.g. ethylboronic acid) in the presence of a suitable base such as K 3 PO 4 and a palladium catalyst like palladium acetate with triphenylphosphine in a solvent such as toluene or dioxane preferably at temperatures between RT and 100°C.
  • a suitable base such as K 3 PO 4
  • a palladium catalyst like palladium acetate with triphenylphosphine
  • solvent such as toluene or dioxane preferably at temperatures between RT and 100°C.
  • Compounds of formula (III), wherein R 5 represents hydrogen, m represents 0, and R 1 represents hydroxy-(C 1 -C 2 )alkyl can be prepared from amino acid derivatives (XXX), wherein R c represents phenyl, which is substituted with R 2 and optionally substituted with one or two R 3 , and R represents (C 1 -C 4 )alkyl (preferably methyl or ethyl), via reduction with LiAlH 4 or BH 3 in a solvent such as THF or by using NaBH 4 in MeOH preferably at temperatures between 0°C and RT to form the respective aminoalcohols (scheme 8).
  • Compounds of formula (IIId), wherein R 5 represents methyl can be synthesized under the methylation conditions as described for the synthesis of compounds of formula (IIIb).
  • Compounds of formula (III), wherein R 5 represents hydrogen, m represents 1 or 2, and R 1 and R 2 together represent -CH 2 CH 2 - or -CH 2 CH 2 CH 2 - can be prepared by reduction of nitriles (XXXIII), wherein q represents 0 or 1 and R 3 represents halogen with H 2 and Raney Nickel as catalyst in a solvent such as NH 3 in MeOH (scheme 9).
  • a reducing agent such as BH 3 in THF preferably at temperatures between 0°C and 65°C or such as LiAlH 4 in a solvent like THF or Et 2 O preferably at temperatures between 0°C and RT can be used to form amines of formula (IIIe), wherein m represents 1 or 2.
  • Nitriles (XXXIII), wherein q represents 0 can be prepared from ketones (XXXI), wherein R 3 represents halogen via a van Leusen reaction utilizing TosMIC and a base like tBuOK in a solvent such as DME/EtOH at temperatures between 0°C and RT.
  • compounds of formula (III), wherein R 1 and R 5 represent hydrogen and m represents 0 can be prepared from aniline derivatives (XXXIV), wherein aryl means phenyl which is substituted with R 2 and optionally substituted with R 3 by a Meerwein arylation type reaction using a Cu(II) salt like CuCl 2 , tBu-nitrite and 1,1-dichloroethylene in a solvent like MeCN followed by refluxing in MeOH in the presence of sodium methoxide and subsequent treatment with concentrated H 2 SO 4 , preferably at a temperature between RT and 90°C (scheme 10).
  • XXXIV aniline derivatives
  • aryl means phenyl which is substituted with R 2 and optionally substituted with R 3 by a Meerwein arylation type reaction using a Cu(II) salt like CuCl 2 , tBu-nitrite and 1,1-dichloroethylene in a solvent like MeCN followed by refluxing in MeOH in the presence of sodium me
  • HPLC-MS analyses were performed on a Thermo MSQ mass spectrometer with a Dionex Ultimate HPG-3000 pump and a Dionex Ultimate 3000 photodiode array detector.
  • Preparative HPLC/MS purifications were performed on a Waters system, equipped with a binary gradient module (2545), a HPLC pump (515), a photodiode array detector (2998) and a mass detector (3100).
  • CC was performed using silica gel 60 Merck (0.063-0.200 mm) or using pre-packed cartridges (SNAP KP-SilTM) from Biotage®.
  • Racemates can be separated into their enantiomers by preparative chiral HPLC.
  • NBS 9.08 g, 51.0 mmol
  • methyl cyclohex-2-enecarboxylate 5.96 g, 42.5 mmol
  • THF/H 2 O 500 mL, 9:1
  • the mixture was allowed to warm to RT and stirred for 2 h.
  • aq. sat. Na 2 S 2 O 3 and aq. sat. NaHCO 3 were added and the mixture was conc. in vacuo.
  • the residue was partitioned between EtOAc and aq. sat. NaHCO 3 .
  • the org. layer was washed multiple times with aq. sat. NaHCO 3 and brine, dried over MgSO 4 , and conc. in vacuo.
  • n-BuLi in hexanes 2.3 M, 10.9 mL, 25.0 mmol
  • DIPA 3.5 mL, 25.0 mmol
  • THF 102 mL
  • the soln. was stirred at -20°C for 30 min, then, it was cooled to -78°C and a soln. of 2,4-dichlorothiazole (3.50 g, 22.7 mmol) in THF (16 mL) was added.
  • the P2X 7 receptor antagonistic activity of the compounds of formula (I) is determined in accordance with the following experimental method.
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CN104918617A (zh) 2015-09-16
CA2896790C (en) 2022-05-10
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US9388197B2 (en) 2016-07-12
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